Vitamin B₁₂: Experiments Concerning the Origin of Its Molecular Structure

Abstract

Following the chemical synthesis of vitamin Biz, a search was begun for a potentially biomimetic "dark" variant of the photochemical A/D-secocorrin -+ corrin cycloisomerization, the central ring-closure step in one of the two cobyric acid syntheses. Significantly, not just one but a whole family of such variants was discovered. According to what is currently known, one of these variants can indeed be regarded as a chemical model for the reaction path followed by Nature in the biosynthetic construction of the corrin ring. These chemical studies of vitamin B l 2 biosynthesis had revealed that the A/D-ring junction, regarded as the main obstacle to a chemical vitamin BI2 synthesis at the outset, is in fact a structural element that is formed readily and in a variety of ways from structurally appropriate precursors. More recent investigations have shown that the same holds for other specific structural elements of the vitamin Bl2 molecule, including the characteristic arrangement of double bonds in the corrin chromophore, the special dimension of the macrocyclic ring of the corrin ligand, the specific attachment of the nucleotide loop to the propionic acid side chain of ring D, and the characteristic constitutional arrangement of the side chains around the ligand periphery (which vitamin B I 2 shares with all uroporphinoid cofactors). All these outwardly complex structural elements are found to "self-assemble" with surprising ease under structurally appropriate preconditions; the amount of "external instruction" required for their formation turns out to be surprisingly small in view of the complexity and specificity of these structural elements. We view these findings as steps on the way toward a chemical rationalization of the vitamin BIZ structure. The goal is to arrive experimentally at a perception of the biomolecule's intrinsic potential for structural self-assembly. This potential, together with the specific type of reactivity related to the biological function, is considered to be responsible for the biomolecule having been chosen by natural selection. The chemical rationalization of the structure of biomolecules is an objective of organic natural product chemistry. The field of natural product synthesis provides appropriate conceptual and methodological tools to approach this objective experimentally. Introduction: Concerning the Origin of Cofactors and the Emergence of Biosynthetic PathwaysThe (organic) cofactors occupy an exquisite position with respect to structure and function among the low-molecular-weight natural products. Their diverse and sometimes quite unusual structures, often occurring in families, are distinguished by their disposition to special types of reactivity. In partnerships between cofactors and specific proteins these dispositions are expressed and functionally exploited to a high degree of perfection with respect to both efficiency and selectivity. This perfection may seem natural to biologists, but it never ceases to surprise and amaze chemists to whom it represents a source of perman...

The cobalamin (coenzyme B12) biosynthetic genes of Escherichia coli

“…On the basis of comparisons of G؉C content, codon usage bias, dinucleotide frequencies, and patterns of synonymous and nonsynonymous substitutions, we conclude that the cob operon was introduced into the Salmonella genome from an exogenous source. The cob operon of E. coli may be related to cobalamin synthetic genes now found among non-Salmonella enteric bacteria.Although commonly touted as one of the largest and oldest of the cofactors participating in modern biochemistry (20,23,59,60), the physiological importance of cobalamin (coenzyme B 12 ), especially among enteric bacteria, has remained enigmatic (58, 63). Cobalamin is derived from uroporphyrinogen III, a precursor in the synthesis of heme, siroheme, and chlorophylls as well as cobamides (Fig.…”

Precorrin-6x reductase from Pseudomonas denitrificans: purification and characterization of the enzyme and identification of the structural gene

“…We inferred from this observation that an enzymatic NADPH-dependent reduction step certainly takes place with precorrin-6x as the substrate. The preparation of the next intermediate after precorrin-6x along the pathway to corrins was therefore attempted by incubating [1,11,17-methyl-14C]precorrin-6x (compound 2b in Fig. 1) with a cell-free protein preparation, with NADPH as the sole cofactor.…”

“…In conclusion, the discovery of precorrin-6x has brought to light the necessity of a reducing step during the biosynthesis of the corrin macrocycle, whereas from a chemical standpoint, vitamin B12 biosynthesis can occur without participation of external redox reagents (11). The isolation of precorrin-6x reductase and the identification of its structural gene has conclusively demonstrated the requirement for this reduction step along the pathway to corrins in P. denitrificans.…”

Shaping RNA Structures with Metal Ions and Metal Ion Complexes

“…derivatives are considered the evolutionary most ancient protein cofactors [82][83][84] and might have already played a role in the so-called RNA world. [85] This ancient relationship between a nucleic acid and this fascinating metal ion complex triggered our interest already some time ago.…”